Abstract 108: Sympathetic Inhibition Prevents the Homing of Specific Memory T Cells to the Bone Marrow and the Development of Repeated Hypertension

Abstract

Effector memory T cells (T EM cells) play a crucial role in hypertension. Formed during an initial blood pressure surge, T EM cells can reside in bone marrow (BM) in a quiescent state for prolonged periods. Upon re-exposure to a hypertensive stimulus, these cells can be reactivated and aggravate hypertension and renal damage. Hypertension is also associated with elevated sympathetic outflow. We hypothesized that sympathetic nerves promote accumulation and reactivation of hypertension-specific T EM cells in the BM. We performed unilateral superior cervical ganglionectomy (SCGx) in C57BL/6 mice, causing sympathectomy of the forelimb on the surgical side. After 2-week Ang II infusion (490 ng/kg/min s.c.), 5х10 6 BM cells from both the SCGx and control limbs were isolated and co-cultured with 0.5х10 6 dendritic cells from other hypertensive mice. We found 30% fewer CD8 + T cell proliferation in the SCGx BM than intact side (1.9±0.2 vs. 2.8±0.1х10 4 , p<0.01), but no difference in CD4 + T cells. To study mechanisms involved in T cell homing, 10 7 pan T cells were isolated from CD45.2 mice after Ang II infusion and adoptively transferred to CD45.1 mice with unilateral SCGx. Flow cytometry indicated that 35% fewer donor CD8 + T EM cells homed to the SCGx than the intact BM 7 days after transfer (5.3±0.8 vs. 8.1±1.5 per 10 4 total T cells, p<0.05). We further determined if systemic sympatho-inhibition during T cell homing is protective against future hypertensive stimuli. We blocked systemic sympathetic outflow by injecting an inhibitory designer receptor exclusively activated by a designer drug (Gi-DREADD) into the rostroventral lateral medulla (RVLM) and performed pan-T cell adoptive transfer 10 days later. The DREADD ligand CNO was given in drinking water 3 days before till 7 days after adoptive transfer. After washout, mice received low dose Ang II infusion (140 ng/kg/min) for 2 weeks. As measured by radiotelemetry, mice with control injection developed hypertension (160±7 mmHg). However, mice with Gi-DREADD expressed in RVLM remained normotensive (136±3 mmHg, p<0.05 vs. control). These data define a novel role of sympathetic nerves in regulation of memory T cell trafficking, and sympathetic inhibition may have long term protective effect beyond lowering blood pressure.